The present invention relates generally to phthalazirie compounds useful as AMPA receptor antagonists, which are useful for the treatment of neuropsychopharmacological disorders such as stroke, ischemia, epilepsy and mood disorders.
In the past fifteen years a great deal of attention has been directed toward the excitatory amino acids (EAA's), glutamate and aspartate, since they are believed to be the neurotransmitter responsible for fast excitatory transmission in the mammalian central nervous system (CNS). At present the ionotropic EAA receptors are generally sub-classified into NMDA and non-NMDA receptors. This classification defines those receptors which preferentially bind N-methyl-D-aspartate (NMDA) and those that are not responsive to NMDA but responsive to .alpha.-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and kainic acid (KA).
Tarnawa et al. describe 2,3-benzodiazepines (Eur. J. Pharmacol., 167:193-199, 1989) which inhibit AMPA stimulated cunents in neuronal cells. The 2,3-benzodiazepines such as GYKI 52466 and 53655 described by Tarnawa are non-competitive AMPA antagonists which bind to a novel modulatory site on the AMPA receptor. Meldrum (Stroke, 23:861, 1992 & Brain Res., 571:115, 1992) has shown that GYKI 52466 was effective in rat models of both global and focal ischemia. GYKI 52466 was effective in a middle cerebral artery occlusion (MCAO) model of ischiemia when given either continuously for 2 hours just after occlusion or ore hour after occlusion. They reduced cortical infarct volumes by 68% and 48% respectively. In another model of neurodegenerative disease, the rat common carotid arteries model of global ischemia, GYKI 52466 was as effective as the glutamate site competitive antagonist NBQX. These animal models suggest that these compounds may be useful for the treatment of stroke and neurodegenerative conditions following ischemia. Parsons and Truner (GB 1,094,044) describe 1-(N-hydroxyamino)-phthalazines which have antipyretic, antiinflammatory, and hypotensive properties.
Efforts to find NMDA receptor antagonists and blockers which are neuroprotective have been very successful while efforts to find specific non-NMDA receptor antagonists have been much less successful. A number of pharmaceutical companies have pursued development of ion channel blockers or full antagonists of the NMDA receptor to protect against both chronic and acute neurodegenerative processes. Although some compounds entered clinical trials there has been only limited progress in developing a clinically useful NMDA receptor antagonist, because the compounds exhibit severe side effects ranging from hallucinations and loss of coordination, to neuronal damage, memory impairment and learning disability. Though non-NMDA antagonists have been shown to be useful in neuroprotective models in animals, there has been little progress in developing a clinically useful AMPA receptor antagonist.
It is an object of the invention to provide compounds which are useful as non-NMDA receptor antagonists as well as methods for their synthesis. It is a further object of the invention to provide non-NMDA receptor antagonists which are useful as sedatives or for the treatment of neuropsychopharmacological disorders such as stroke, ischemia, epilepsy and mood disorders. It is yet another object of the invention to provide compounds which are useful for the treatment of neurological, neuropsychiatric, neurogenerative, and functional disorders associated with excessive activation of the non-NMDA subtypes of the ionotropic EAA receptor, particularly the AMPA subtype.